Next generation sequencing is providing new hope for understanding metastatic renal cancer

Takeaway: If caught early, survival rates for renal cancer patients are positive. However, understanding why cancer in some patients later metastasizes has remained a challenge. New research provides insights that may facilitate more accurate ctDNA analysis and real-time disease monitoring.  

What is Renal Cancer? 

As defined by the National Kidney Foundation, renal cancer is a disease that starts in the kidneys, either in one or both organs, and develops when otherwise healthy cells begin to divide excessively and ultimately form a tumor.

What is the impact of this disease? Updated data from the American Cancer Society outlines key statistics for 2022: 

• 79,000 new cases of kidney cancer will be diagnosed, with about 60% of cases among males 

• 13,920 people will lose their battle with this disease, nearly 65% of whom will be men  
• Diagnosis is twice as common in men than women 
• Average age at diagnosis is 64; it is uncommon in individuals under 45 
• Ranks among the 10 most common cancers; cases have been rising since the early 1990s, but appear to have plateaued during the last several years 

Renal Cancer Survival Rate 

If caught early, survival rates for patients are relatively positive. However, challenges remain when attempting to develop more precise diagnostics to arm physicians with the tools to explain why cancer in some patients later relapses or metastasizes.  

Historical Next Generation Sequencing in Renal Cell Carcinoma (RCC)

While prior research outlined the potential benefit of additional investigation into how both healthy and tumor cells develop, the shift toward liquid biopsy samples has led to a heightened interest in tools capable of working with these low-input samples to help offer insights into cancer control, progression, and metastasis. While the adoption of DNA barcoding methods such as unique molecular identifiers paired with deep next generation sequencing technology has improved sensitivity for tumor detection, researchers attribute the lack of significant advancement toward improved prognosis to two remaining hurdles:

• Lack of an existing commercially available assay to detect low allele frequency tumor DNA from liquid biopsies taken from patients with RCC 
• Low concentration of cell-free (cf) DNA combined with low proportions of circulating tumor (ct) DNA within the cfDNA 

Significant step forward with the help of NGS

A recent study sought to eliminate these barriers by developing a new tool to pinpoint somatic mutations in both tumor tissue and liquid biopsy samples. If successful, this solution would provide biomarker reference data to enable physicians to monitor disease progression in real-time. 

With the assistance of xGen™ NGS, the team of Canadian researchers designed and optimized a new next generation sequencing assay and bioinformatic workflow with the goal of being able to perform dual analysis of genomic (g)DNA and cfDNA to support the comparison between the statuses of somatic mutations in tumors and liquid biopsy samples.  

Using this newly developed assay to interrogate mouse blood samples, the team was able to target RCC and successfully pinpoint the VHL mutation, a known biomarker for RCC. Applying the same approach, researchers tested their design on patient-matched tumor and liquid biopsies provided by the McGill RCC biobank with the intent to duplicate the same identification within both cf- and evDNA fractions. Once again, the team was able to capture RCC-relevant somatic mutations in both primary ctDNA and evDNA of patients with initial and advanced tumors.

An interesting outcome of this analysis is that, although it is well established that soluble ctDNA (found in cfDNA) can carry the signatures of the disease, researchers were able to demonstrate that ctDNA encapsulated in EVs is another potentially important source of genetic signatures for RCC. The proposed extra stability and larger fragment sizes of evDNA, while still under investigation, may lead to more robust assays in the future. 

What is next for renal cancer research? 

Collectively, these findings enhance our shared efforts to understand tumor presence and complexity within renal cancer, and their RCC-specific sequencing assay and workflow serve as a proof of principle for detecting tumor-specific mutations in liquid biopsies of RCC patients. The overall success of the study marks a significant step of progression for precision oncology in RCC as these new tools set the stage to begin facilitating more accurate disease analysis and monitoring. 

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